Prostaglandin E analogues

ABSTRACT

A prostaglandin analog represented by Formula (I):                    
     [wherein A is an ethylene group, a vinylene group or an ethynylene group, Y 1  and Y 2  are the same or different, and each a hydrogen atom, a halogen atom, a cyano group, —CONR 3 R 4  (wherein R 3  and R 4  are the same or different, and each a hydrogen atom or a C 1-6  alkyl group, or R 3  and R 4  together with the nitrogen atom to which they are attached form a C 4-8  cyclic amine), a C 1-3  aminoalkyl group, a C 1-6  hydroxyalkyl group, NR 5 R 6  (wherein R 5  and R 6  are the same or different, and each a hydrogen atom or a C 1-6  alkyl group), a hydroxyl group, a C 1-6  alkoxy group, a C 1-9  alkyl group, a C 1-6  alkyl group substituted with halogen(s), a C 1-5  acyl group or COOR 7  (wherein R 7  is a hydrogen atom, a C 1-6  alkyl group or a phenyl group), R 1  and R 2  are the same or different, and each a hydrogen atom, a halogen atom, a C 1-9  alkyl group or a C 1-6  alkyl group substituted with halogen(s), m is an integer of 0 to 6, and n is an integer of 0 to 3], a pharmaceutically acceptable salt thereof or a hydrate thereof.

TECHNICAL FIELD

The present invention relates to an excellent pharmaceutical preparationfor prevention or treatment of the restenosis after percutaneoustransluminal coronary angioplasty (PTCA) which comprises as an effectiveingredient a prostaglandin analog, a pharmaceutically acceptable saltthereof or a hydrate thereof.

BACKGROUND ART

Since PG (hereinafter PG represents prostaglandin) exhibits variousimportant physiological actions, the syntheses of a great number of thederivatives and the biological activities have been investigated andhave been reported in many literatures, for example, Japanese PatentKokai No. 52-100446 and U.S. Pat. No. 4,131,738.

PG and the derivatives thereof have biological actions such as avasodilating action, a prophlogistic action, an inhibitory action ofblood platelet aggregation, a uterine muscle contraction action, anintestine contraction action or a lowering action of intraocularpressure, and are useful for treatment or prevention of myocardialinfarction, angina pectoris, arteriosclerosis, hypertension or duodenalulcer, and further useful for labor induction, artificial termination ofpregnancy, etc.

On the other hand, PTCA has low invasiveness to the patient as atherapeutic modality of ischemic heart diseases and has an excellentinitial treatment effect, therefore, it is a plasty which recently hasrapidly been developed. However, there has been an unsolved drawback ofcausing restenosis of coronary artery at a frequency of 30-40% within afew months after PTCA.

The compounds which can control not only the migration from intima tomesothelium of vascular smooth muscle cells deeply associating with theonset of restenosis but also their growth in the mesothelium are greatlyexpected as drugs for prevention of the restenosis. However, noclinically available drugs have been found.

An object of the present invention is to provide a pharmaceuticalpreparation for prevention or treatment of the restenosis after PTCAwhich exhibits an inhibiting action on the growth of vascular smoothmuscle.

DISCLOSURE OF THE INVENTION

As a result of the continued extensive studies, the present inventorshave found that a prostaglandin analog represented by the followingFormula (I) exhibits a characteristic inhibiting action on the growth ofvascular smooth muscle, and thereby the present invention has beenaccomplished.

That is, the present invention is directed to a prostaglandin analogrepresented by Formula (I):

[wherein A is an ethylene group, a vinylene group or an ethynylenegroup, Y¹ and Y² are the same or different, and each a hydrogen atom, ahalogen atom, a cyano group, a C₁₋₃ aminoalkyl group, a C₁₋₆hydroxyalkyl group, NR⁵R⁶ (wherein R⁵ and R⁶ are the same or different,and each a hydrogen atom or a C₁₋₆ alkyl group), a hydroxyl group, aC₁₋₆ alkoxy group, a C₁₋₉ alkyl group, a C₁₋₆ alkyl group substitutedwith halogen(s) or a C₁₋₅ acyl group, R¹ and R² are the same ordifferent, and each a hydrogen atom, a halogen atom, a C₁₋₉ alkyl groupor a C₁₋₆ alkyl group substituted with halogen(s), m is an integer of 0to 6, and n is an integer of 0 to 3], a pharmaceutically acceptable saltthereof or a hydrate thereof.

MODE FOR CARRYING OUT THE INVENTION

In the present invention, the vinylene group means a cis- ortrans-vinylene group.

The halogen atom refers to a fluorine atom, a chlorine atom, a bromineatom or an iodine atom, and preferably a fluorine atom or a chlorineatom.

The C₁₋₃ aminoalkyl group means a straight or branched aminoalkyl grouphaving 1 to 3 carbon atoms, examples of which are an aminomethyl group,an aminoethyl group and an aminopropyl group, and preferably anaminomethyl group.

Examples of the C₄₋₈ cyclic amine are pyrrolidine, piperidine andmorpholine, and preferably piperidine.

The C₁₋₆ hydroxyalkyl group means a straight or branched hydroxyalkylgroup having 1 to 6 carbon atoms, examples of which are a hydroxymethylgroup, a dimethylhydoxymethyl group and a dihydroxymethyl group.

The C₁₋₆ alkoxy group means a straight or branched alkoxy group having 1to 6 carbon atoms, examples of which are a methoxy group, an ethoxygroup and a propoxy group.

The C₁₋₆ alkyl group substituted with halogen(s) means a straight orbranched alkyl group having 1 to 6 carbon atoms which is substitutedwith fluorine atom(s), chlorine atom(s), bromine atom(s) or iodine(s),and is preferably a perfluoroalkyl group, and more preferably atrifluoromethyl group.

The C₁₋₆ alkyl group means a straight or branched alkyl group having 1to 6 carbon atoms, and examples of which are a methyl group, an ethylgroup, a propyl group, an isopropyl group, a butyl group, an isobutylgroup, a tert-butyl group, a pentyl group, an isopentyl group, a2-ethylpropyl group, a hexyl group, an isohexyl group and a 1-ethylbutylgroup.

The C₁₋₉ alkyl group means the above-mentioned C₁₋₆ alkyl group and astraight or branched C₇₋₉ alkyl group means, example of which are aheptyl group, an octyl group and a nonyl group.

The C₁₋₅ acyl group means a straight or branched alkanoyl, alkenoyl oralkynoyl group having 1 to 5 carbon atoms, examples of which are anacetyl group, a propionyl group, a crotonoyl group and a propioloylgroup.

Examples of the pharmaceutically acceptable salt are salts with alkalimetals (e.g., sodium or potassium), alkali earth metals (e.g., calciumor magnesium), ammonia, methylamine, dimethylamine, cyclopentylamine,benzylamine, piperidine, monoethanolamine, diethanolamine,monomethylmonoethanolamine, tromethamine, lysine, a tetraalkyl ammoniumor tris(hydroxymethyl)aminomethane.

When Y¹ or Y² is NR⁵R⁶, R⁵ and R⁶ are preferably each a methyl group.

The compounds of Formula (I) of the present invention can bespecifically prepared, for example, by the methods summarized by thefollowing reaction scheme.

In the reaction scheme, TBS is a tert-butyldimethylsilyl group, A′ is anethylene group or a vinylene group, Et is an ethyl group, A, Y¹, Y², R¹,R², m and n are as defined above.

The above-mentioned reaction scheme is illustrated as follows:

(1) At first, a known compound of Formula (II) is reacted with 0.8 to2.0 equivalents of a compound represented by Formula (III) or (IV) in aninert solvent (e.g., benzene, toluene, tetrahydrofuran, diethyl ether,methylene chloride or n-hexane) at −78 to 30° C. according to the methodof Sato et al. (Journal of Organic Chemistry, vol. 53, page 5590 (1988))to stereospecifically give a compound of Formula (V). Herein, thecompound wherein A is an ethylene group or a vinylene group (i.e., thecompound wherein A is A′) can be obtained by a reaction using a compoundof Formula (III) at −78 to 0° C., and the compound wherein A is anethynylene group can be obtained by a reaction using a compound ofFormula (IV) at 0 to 30° C.

The organic copper compound of Formula (III) used as a material can beprepared, for example, according to a method shown by the followingreaction scheme.

In the reaction scheme, A′, R¹, R² and TBS are as defined above.

That is, an aldehyde compound represented by Formula (VIII) is reactedwith methyl (triphenylphosphoranilidene)acetate in an inert solvent(e.g., methylene chloride, benzene, toluene or xylene) at 0° C. to areflux temperature of the solvent, followed by a reaction using areductant such as diisobutylaluminum hydride to give a compound ofFormula (IX).

Subsequently, the compound of Formula (IX) is subjected to astereoselective oxidation reaction using diisopropyl L-(+)-tartrate andtitanium tetraisopropoxide in tert-butyl hydroperoxide and methylenechloride at −20° C. to give an epoxy compound. The resulting epoxycompound is subjected to methanesulfonylation and substitution withlithium chloride, successively, to give a compound of Formula (X).

The compound of Formula (X) is reacted with n-butyl lithium intetrahydrofuran at −70° C. to give an acetylene derivative, the hydroxylgroup of which is then protected. in an ordinary manner, thereby acompound of Formula (XI) is obtained.

The compound of Formula (XI) is reacted in an amount of 0.5 to 4equivalents with 1 to 5 equivalents of a radical reductant (e.g.,trimethyltin hydride, tributyltin hydride or triphenyltin hydride) inthe presence of 0.05 to 2 equivalents of a radical generating agent(e.g., azobisisobutyronitrile, azobiscyclohexanecarbonitrile, benzoylperoxide or triethyl borane) at −78 to 100° C., and then reacted withiodine in a mixture of diethyl ether and a saturated aqueous sodiumbicarbonate solution to give a compound of Formula (XII).

The compound of Formula (XII) is subjected to a reaction with tert-butyllithium and then subjected to a reaction with lithium2-thienylcyanocuprate to give a compound of Formula (III).

(2) The compound of Formula (V) is reacted with 0.5 to 4 equivalents ofan organic copper compound represented by Formula (VI) and 0.5 to 4equivalents of trimethylchlorosilane in an inert solvent (e.g., benzene,toluene, tetrahydrofuran, diethyl ether, methylene chloride, n-hexane orn-pentane) at −78 to 40° C., followed by hydrolysis using an inorganicacid (e.g., hydrochloric acid, sulfuric acid or nitric acid), an organicacid (e.g., acetic acid or p-toluenesulfonic acid) or an amine saltthereof (e.g., pyridinium p-toluenesulfonate) in an organic solvent(e.g., acetone, methanol, ethanol, isopropanol, diethyl ether or amixture thereof) at 0 to 40° C. to stereoselectively give a compound ofFormula (VII).

Furthermore, the compound of Formula (V) is reacted with 0.5 to 4equivalents of a compound represented by Formula (VI′), 0.05 to 2equivalents of a radical generating agent (e.g., azobisisobutyronitrile,azobiscyclohexanecarbonitrile, benzoyl peroxide or triethyl borane) and1 to 5 equivalents of a radical reductant (e.g., tributyltin hydride,triphenyltin hydride, dibutyltin hydride or diphenyltin hydride) in aninert solvent (e.g., benzene, toluene, xylene, n-hexane, n-pentane oracetone) at −78 to 100° C. to give a compound of Formula (VII).

(3) The tert-butyldimethylsilyl group (i.e., a protective group of thehydroxyl group) of the compound of Formula (VII) is removed by usinghydrofluoric acid, pyridinium poly(hydrogenfluoride) or hydrochloricacid under conventional conditions in a solvent (e.g., methanol,ethanol, acetonitrile, a mixture thereof or a mixture of these solventsand water) to give a PG analog of Formula (I) of the present invention.

The compounds of the present invention can be administered systemicallyor topically, or orally or parenterally such as rectally,subcutaneously, intramuscularly, intravenously or percutaneously, andpreferably orally or intravenously. For example, they can beadministered orally in the form such as tablets, powders, granules,dusting powders, capsules, solutions, emulsions or suspensions, each ofwhich can be prepared according to conventional methods. As the dosageforms for intravenous administration, there are used aqueous ornon-aqueous solutions, emulsions, suspensions or solid preparations tobe dissolved in a solvent for injection immediately before use.Furthermore, the compounds of the present invention can be formulatedinto the form of inclusion compounds with α-, β- or γ-cyclodextrin, ormethylated cyclodextrin. In addition, the compounds of the presentinvention can be administered by injection in the form of aqueous ornon-aqueous solutions, emulsions, suspensions, etc. The dose is variedby the age, body weight, etc., but it generally is from 1 ng to 1 mg/dayper adult, which can be administered in a single dose or divided doses.

Representative compounds of Formula (I) of the present invention areshown as follows.

Compound A m n Y¹ Y² R¹ R²  1 ethylene 2 2 4-CO₂Me H H H  2 ethylene 2 14-CO₂H H H H  3 ethylene 2 2 4-CO₂H H H H  4 ethylene 2 3 4-CO₂H 3-Me HH  5 ethylene 2 2 4-CF₃ H H H  6 ethylene 3 2 4-OMe H H H  7 ethylene 12 4-N(Me)₂ H 4-CF₃ H  8 trans-vinylene 2 2 2-CO₂Me H H H  9trans-vinylene 2 2 3-CO₂Me H H H 10 trans-vinylene 2 2 4-CO₂Me H H H 11cis-vinylene 2 2 4-CO₂Me H H H 12 trans-vinylene 2 2 4-CO₂H H H H 13trans-vinylene 2 2 4-CO₂H 3-Me H H 14 trans-vinylene 2 2 4-CO₂H H 2-Cl4-Cl 15 trans-vinylene 2 2 4-CO₂H H 3-CF₃ 5-CF₃ 16 trans-vinylene 2 22-CF₃ H H H 17 trans-vinylene 2 2 3-CF₃ H H H 18 trans-vinylene 2 24-CF₃ H H H 19 cis-vinylene 2 2 4-CF₃ H H H 20 trans-vinylene 2 2 4-CF₃H 2-Cl 4-Cl 21 trans-vinylene 2 2 4-CF₃ H 4-Me H 22 trans-vinylene 3 14-Me H H H 23 trans-vinylene 3 1 4-Me H 2-CF₃ 4-CF₃ 24 trans-vinylene 31 4-Me H 3-CF₃ 5-CF₃ 25 trans-vinylene 3 2 4-Me H H H 26 trans-vinylene3 2 4-Me H 3-CF₃ H 27 trans-vinylene 2 2 2-Me H H H 28 trans-vinylene 22 3-Me H H H 29 trans-vinylene 2 2 4-Me H H H 30 trans-vinylene 2 2 2-Me6-Me 4-Cl H 31 trans-vinylene 2 2 4-COMe H H H 32 cis-vinylene 2 24-COMe H H H 33 trans-vinylene 1 2 H H H H 34 trans-vinylene 2 1 H H H H35 trans-vinylene 2 1 H H 3-CF₃ 5-CF₃ 36 trans-vinylene 2 2 H H H H 37trans-vinylene 3 1 H H H H 38 trans-vinylene 3 2 H H H H 39 cis-vinylene2 2 H H H H 40 cis-vinylene 3 2 H H H H 41 trans-vinylene 3 2 4-OMe H HH 42 cis-vinylene 3 2 4-OMe H H H 43 trans-vinylene 2 2 4-OMe H H H 44trans-vinylene 3 2 4-OH H H H 45 trans-vinylene 2 2 4-OH H H H 46trans-vinylene 2 1 4-F H H H 47 cis-vinylene 2 1 4-F H H H 48trans-vinylene 2 2 2-F H H H 49 trans-vinylene 2 2 3-F 5-F H H 50trans-vinylene 2 2 4-F H H H 51 trans-vinylene 2 2 2-Cl H H H 52trans-vinylene 2 2 3-Cl 5-Cl H H 53 trans-vinylene 2 2 4-Cl H H H 54trans-vinylene 3 2 4-CH₂OH H H H 55 trans-vinylene 2 2 4-CH₂OH H H H 56cis-vinylene 2 2 4-N(Me)₂ H H H 57 trans-vinylene 2 2 4-N(Me)₂ H H H 58trans-vinylene 1 2 4-N(Me)₂ H 2-CF₃ H 59 trans-vinylene 1 2 4-N(Me)₂ H3-CF₃ H 60 trans-vinylene 1 2 4-N(Me)₂ H 4-CF₃ H 61 trans-vinylene 2 24-N(Me)₂ H 2-CF₃ H 62 trans-vinylene 2 2 4-N(Me)₂ H 3-CF₃ H 63trans-vinylene 2 2 4-N(Me)₂ H 4-CF₃ H 64 trans-vinylene 2 2 4-N(Me)₂ H2-F H 65 trans-vinylene 2 2 4-N(Me)₂ H 3-F H 66 trans-vinylene 2 24-N(Me)₂ H 4-F H 67 trans-vinylene 2 2 4-N(Me)₂ H 2-Cl H 68trans-vinylene 2 2 4-N(Me)₂ H 3-Cl H 69 trans-vinylene 2 2 4-N(Me)₂ H4-Cl H 70 trans-vinylene 2 2 4-Piperdi-CO H H H 71 trans-vinylene 2 24-C(OH)(Me)₂ H 2-CF₃ H 72 trans-vinylene 2 2 4-C(OH)(Me)₂ H 3-CF₃ H 73trans-vinylene 2 2 4-C(OH)(Me)₂ H 4-CF₃ H 74 ethynylene 2 2 4-CO₂Me H HH 75 ethynylene 2 2 4-CO₂H H H H 76 ethynylene 2 2 2-CF₃ H H H 77ethynylene 2 2 3-CF₃ 5-CF₃ H H 78 ethynylene 2 1 4-CF₃ H H H 79ethynylene 2 2 4-CF₃ H H H 80 ethynylene 3 2 4-Me H H H 81 ethynylene 32 4-Me H 3-CF₃ H 82 ethynylene 2 2 4-CH₂OH H H H 83 ethynylene 2 24-N(Me)₂ H H H 84 ethynylene 2 2 4-C(OH)(Me)₂ H 4-CF₃ H 85 ethynylene 22 4-COMe H H H Piperdi-CO: piperidinocarbonyl

INDUSTRIAL APPLICABILITY

The compounds of the present invention exhibit an excellent inhibitingaction on the growth of vascular smooth muscle cells and have lowside-effects, therefore, they are useful as a-drug for inhibition ofvascular thickening (e.g. a cause of restenosis after percutaneoustransluminal coronary angioplasty) and vascular occlusion, or useful asa drug for prevention or treatment of vascular thickening and vascularocclusion.

BEST MODE FOR CARRYING OUT THE INVENTION

The present invention is illustrated in more details by the followingexamples and reference example, but it is not limited by thesedescriptions. In the nomenclature of the compound such as, for example,2,3,4-trinor-1,5-inter-m-phenylene, “nor” means the lack of a carbonchain at the position of interest, (i.e., in the above case, it meansthe lack of carbon chains at the 2-, 3- and 4-positions), and“inter-phenylene” means the insertion of a benzene ring between thecarbon atoms (i.e., in the above case, it means that each of the carbonatoms at the 1- and 5-positions binds to the benzene ring at themeta-position).

Reference Example 1(1E,3S)-1-Iodo-3-(tert-butyldimethylsiloxy)-5-phenyl-1-pentene

(1) To a methylene chloride solution (200 ml) of hydrocinnamaldehyde(25.64 g) was added methyl (triphenylphosphoranilidene)acetate (63.9 g)at 0° C., followed by stirring at room temperature overnight. Theinsoluble substance was removed by filtration, the filtrate wasconcentrated, and the resulting residue was purified by a silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate=30:1) togive methyl (2E)-5-phenyl-2-pentenoate (30.22 g).

¹H-NMR(200 MHz, CDCl₃) δ ppm: 2.44-2.60(m,2H), 2.72-2.84(m,2H),3.72(s,3H), 5.85(dt,J=15.7,1.6 Hz,1H), 7.01(dt,J=15.7,6.8 Hz,1H),7.12-7.37(m,5H)

IR(neat):3063,3028,2949,2858,1724,1658,1604,1497,1455,1436,1320,1237,1203,1151,1088,1041,979,913,854,750,700 cm⁻¹

(2) To a diethyl ether solution (200 ml) of the compound obtained in theabove (1) (19.37 g) was added diisobutylaluminum hydride (1.5 M, toluenesolution, 149.4 ml) at −70° C., followed by stirring at room temperaturefor 1.5 hours. The mixture was made acidic with hydrochloric acid withice-cooling, and the organic layer was washed with a saturated aqueoussodium bicarbonate solution and a saturated aqueous sodium chloridesolution. The organic layer was dried over anhydrous magnesium sulfateand concentrated, and the resulting crude product was evaporated underreduced pressure to give (2E)-5-phenyl-2-penten-1-ol (13.9 g).

b.p.91.5˜92.0° C./0.56 torr.

¹H-NMR(200 MHz, CDCl₃) δ ppm: 1.20-1.60(br s,1H), 2.30-2.44(m,2H),2.69(d,J=8.4 Hz,1H), 2.72(d,J=9.5 Hz,1H), 4.08(d,J=4.6 Hz,2H),5.57-5.83(m,2H), 7.12-7.36(m,5H)

IR(neat):3339,3027,2927,2857,1964,1873,1806,1670,1604,1496,1455,1385,1221,1155,1084,1000,970,747,699 cm⁻¹

(3) To a mixture of powder Molecular Sieves 4A (8.2 g), titaniumtetraisopropoxide (5.1 ml) and methylene chloride (125 ml) was addeddropwise diisopropyl L-(+)-tartrate (4.4 ml) under an argon stream at−20° C., followed by stirring under the same conditions for 30 minutes.Then, a methylene chloride solution (41 ml) of the compound obtained inthe above (2) (13.9 g) was added and stirred at −20° C. for an hour. Themixture was cooled to −30° C., and tert-butyl hydroperoxide (3.2 M,methylene chloride solution, 48.3 ml) was added dropwise over 30minutes. After the completion of the addition, stirring was continued at−20° C. for 18 hours, and dimethyl sulfide (14 ml) was added, followedby stirring at the same temperature for 3 hours. Then, an aqueoustartaric acid solution (10%, 9.3 ml) was added, successively followed bystirring at room temperature for an hour, addition of sodium fluoride(60 g), stirring for an hour, addition of Celite (34 g) and diethylether (96 ml), and stirring for an hour. Filtration and concentrationgave an oily substance (41.9 g), which was then dissolved in diethylether (109 ml), and an aqueous sodium hydroxide solution (1N, 60 ml) wasadded, followed by stirring at room temperature for 1.5 hours. Theorganic layer was separated, the aqueous layer was extracted withdiethyl ether, and the organic layers were combined, washed with asaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated. The resulting residue was purifiedby a silica gel column chromatography (developing solvent; hexane:ethylacetate=1:1) to give (2S,3S)-2,3-epoxy-5-phenyl-1-pentanol (14.2 g).

¹H-NMR(200 MHz, CDCl₃) δ ppm: 1.70(dd,J=7.4,5.6 Hz,1H), 1.83-1.98(m,2H),2.64-2.93(m,3H), 2.99(dt,J=2.6 Hz,5.8 Hz,1H), 3.56(ddd,J=12.6,7.4,4.4Hz,1H), 3.84(ddd,J=12.6,5.6,2.6 Hz,1H), 7.14-7.36(m,5H)

IR(neat):3401,3027,2928,2862,1603,1496,1455,1203,1093,1029,989,880,751,701 cm⁻¹

(4) To a methylene chloride solution (150 ml) of the compound obtainedin the above (3) (14.1 g) and methanesulfonyl chloride (6.8 ml) wasadded dropwise triethylamine (13.3 ml) with ice-cooling. After theaddition, the mixture was stirred at room temperature for 30 minutes,and washed with water, a saturated aqueous sodium bicarbonate solutionand a saturated aqueous sodium chloride solution. The organic layer wasdried over anhydrous magnesium sulfate and concentrated to give(2S,3S)-2,3-epoxy-1-methanesulfonyloxy-5-phenylpentane (20.0 g).

¹H-NMR(200 MHz, CDCl₃) δ ppm : 1.84-1.99(m,2H), 2.64-3.02(m,4H),3.04(s,3H), 4.05(dd,J=11.9,6.2 Hz,1H), 4.39(dd,J=11.9,2.9 Hz,1H),7.13-7.37(m,5H)

IR(neat):3027,2940,1603,1496,1455,1358,1176,958,816,702, 529 cm⁻¹

(5) An N,N-dimethylformamide solution (110 ml) of the compound obtainedin the above (4) (19.5 g) and lithium chloride (6.44 g) was stirredunder an argon stream with heating at 55° C. for 2.5 hours. Aftercooling, water (35 ml) and a saturated aqueous sodium chloride solution(105 ml) were added and, after extraction with ethyl acetate: hexane(1:1), the organic layer was washed with an saturated aqueous sodiumchloride solution. The organic layer was dried over anhydrous magnesiumsulfate and concentrated, and the resulting residue was purified by asilica gel column chromatography (developing solvent; hexane:ethylacetate=20:1) to give (2R,3S)-l-chloro-2,3-epoxy-5-phenylpentane (14.2g).

¹H-NMR(200 MHz, CDCl₃) δ ppm : 1.82-1.98(m,2H), 2.62-3.01(m,4H),3.45(dd,J=11.8,5.0 Hz,1H), 3.54(dd,J=11.8,5.8 Hz,1H), 7.14-7.36(m,5H)

IR(neat):3063,3027,2989,2945,2861,1604,1496,1455,1428,1385,1266,1180,1031,923,875,751,731,700 cm⁻¹

(6) To a tetrahydrofuran solution (67 ml) of the compound obtained inthe above (5) (13.5 g) was added dropwise n-butyl lithium (2.5 M, hexanesolution, 82.4 ml) under an argon stream at −70° C. After the addition,stirring was continued under the same conditions for 30 minutes, and asaturated aqueous ammonium chloride solution (84 ml) was added, followedby extraction with ethyl acetate. The organic layer was washed with asaturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate and concentrated, and the resulting crude product waspurified by a silica gel column chromatography (developing solvent;hexane:ethyl acetate=5:1) to give (3S)-5-phenyl-1-pentyn-3-ol (10.96 g).

¹H-NMR(200 MHz, CDCl₃) δ ppm : 1.94-2.14(m,2H), 2.50(d,J=2.2 Hz,1H),2.74-2.86(m,2H), 4.28-4.44(m,1H), 7.12-7.36(m,5H)

IR(neat):3294,3063,3027,2929,2863,2115,1604,1497,1455,1044, 1013,747,700cm⁻¹

(7) To an N,N-dimethylformamide solution (67 ml) of the compoundobtained in the above (6) (10.9 g) and imidazole (9.3 g) was addedtert-butyldimethylchlorosilane (12.3 g) with ice-cooling, followed bystirring at room temperature overnight. The mixture was poured into asaturated aqueous sodium bicarbonate solution (300 ml), followed bystirring at room temperature for 15 minutes. After extraction withhexane, the organic layer was washed with a saturated aqueous sodiumbicarbonate solution and a saturated aqueous sodium chloride solution.The organic layer was dried over anhydrous magnesium sulfate andconcentrated. The resulting residue was evaporated under reducedpressure to give (3S)-3-(tert-butyldimethylsiloxy)-5-phenyl-1-pentyne(16.2 g).

b.p.108° C./1.8 torr.

¹H-NMR(200 MHz, CDCl₃) δ ppm : 0.10(s,3H), 0.13(s,3H), 0.91(s,9H),1.90-2.08(m,2H), 2.75(d,J=9.5 Hz,1H), 2.78(d,J=9.2 Hz,1H), 4.37(dt,J=2.0Hz,6.3 Hz, 1H), 7.11-7.35(m,5H)

IR(neat):3309,2955,2930,2858,2113,1605,1497,1472,1463,1387,1362,1253,1095,1006,977,940,837,778,699 cm⁻¹

(8) A mixture of the compound obtained in the above (7) (34.27 g),tributyltin hydride (50 g) and azobisisobutyronitrile (20 mg) wasstirred under an argon stream at 160° C. for an hour. After cooling toroom temperature, evaporation under reduced pressure gave the crudeproduct (75.8 g).

(9) To a mixture of the compound obtained in the above (8) (75.8 g),diethyl ether (496 ml) and a saturated aqueous sodium chloride solution(496 ml) was added dropwise a tetrahydrofuran solution (20 ml) of iodine(37.43 g) at 0° C. After the addition, the mixture was stirred at thesame temperature for 30 minutes, and an aqueous sodium thiosulfatesolution was added, followed by extraction with hexane. The organiclayer was washed with a saturated aqueous sodium chloride solution,dried over anhydrous magnesium sulfate and concentrated. The resultingresidue was dissolved in methylene chloride (670 ml), and potassiumfluoride (38.92 g) and water (12.1 ml) were added, followed byvigorously stirring at room temperature for an hour. Anhydrous magnesiumsulfate was added and, after filtration, concentration gave the residue,which was then evaporated under reduced pressure to give the titlecompound (29.8 g).

b.p. 130-140° C./0.60 torr.

¹H-NMR(CDCl₃,200 MHz) δ ppm ;0.03(s,3H), 0.05(s,3H), 0.91(s,9H),1.72-1.90(m,2H), 2.54-2.73(m,2H), 4.07-4.21(m,1H), 6.24(dd,J=14.4,1.1Hz,1H), 6.56(dd,J=14.4,6.0 Hz,1H), 7.11-7.34(m,5H)

EXAMPLE 1

2,3,4,18,19,20-Hexanor-1,5-inter-p-phenylene-17-phenyl-PGE₁ methyl ester(Compound 10)

(1) To a diethyl ether solution (295 ml) of(1E,3S)-1-iodo-3-(tert-butyldimethylsiloxy)-5-phenyl-1-pentene (29.7 g)was added tert-butyl lithium (2.13 M, pentane solution, 69 ml) at −78°C., followed by stirring at the same temperature for 40 minutes. To thesolution was added lithium 2-thienylcyanocuprate (0.25 M,tetrahydrofuran solution, 344 ml) at −78° C., followed by stirring atthe same temperature for 30 minutes. To the solution was added dropwise(4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)cyclopent-2-en-1-one(0.25 M, diethyl ether solution, 246 ml) at −78° C., and the temperaturewas raised to 0° C. over about 1.5 hours.

The reaction solution was poured into a mixture of hexane (600 ml) and asaturated aqueous ammonium chloride solution (600 ml) with stirring, theorganic layer was separated, and the aqueous layer was extracted withhexane (300 ml). The resulting organic layers were dried over anhydrousmagnesium sulfate and filtered. The filtrate was concentrated underreduced pressure, and the resulting crude product was purified by asilica gel column chromatography (developing solvent; hexane:ethylacetate=49:1) to give(3R,4R)-2-methylene-3-[(1E,3S)-3-(tert-butyldimethylsiloxy)-5-phenylpent-1-enyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one(20.42 g).

¹H-NMR(CDCl₃,200 MHz) δ ppm ;0.03(s,3H), 0.07(s,9H),0.87(s,9H),0.92(s,9H),1.70-1.93(m,2H), 2.34(dd,J=18.0,6.8 Hz,1H), 2.50-2.76(m,3H),3.24-3.40(m,1H), 4.02-4.29(m,2H), 5.24(dd,J=2.5,1.0 Hz,1H),5.53(ddd,J=15.5,7.0,0.9 Hz,1H), 5.69(dd,J=15.5,4.9 Hz,1H),6.12(dd,J=3.0,1.0 Hz,1H), 7.10-7.34(m,5H)

IR(neat);3086,3064,3028,2954,2929,2857,1734,1642,1605,1497,1472,1463,1405,1386,1362,1253,1187,1086,1032,1006,991,972,940,922,837,776,748,699,679,590 cm⁻¹

(2) Under an argon stream, copper (I) cyanide-dilithium dichloride (1.0M, tetrahydrofuran solution, 53.1 ml) was added to2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide (0.95 M,tetrahydrofuran solution, 64.5 ml) at −70° C., followed by stirring atthe same temperature for 20 minutes. To the solution were added thecompound obtained in the above (1) (0.25 M, diethyl ether solution, 163ml) and chlorotrimethylsilane (11.0 ml) at −70° C., and the temperaturewas raised to 0° C. with stirring over about an hour. To the reactionsolution was added a saturated aqueous ammonium chloride solution,followed by extraction with hexane. The organic layer was washed with asaturated aqueous sodium bicarbonate solution and a saturated aqueoussodium chloride solution, dried over anhydrous magnesium sulfate,filtered and concentrated. The resulting residue was dissolved indiethyl ether (40.8 ml)-isopropyl alcohol (163.2 ml), and pyridiniump-toluenesulfonate (100 mg) was added, followed by stirring at roomtemperature for 12 hours. The reaction solution, after addition ofhexane, was washed with a saturated aqueous sodium bicarbonate solutionand a saturated aqueous sodium chloride solution, dried over anhydrousmagnesium sulfate, filtered and concentrated, and the resulting residuewas purified by a silica gel column chromatography (developing solvent;hexane:ethyl acetate=15:1) to give2,3,4,18,19,20-hexanor-1,5-inter-p-phenylene-17-phenyl-PGE₁ methyl ester11,15-bis(tert-butyldimethylsilyl ether) (16.75 g).

¹H-NMR(CDCl₃,200 MHz) δ ppm ;0.01(s,6H), 0.05(s,6H), 0.87(s,9H),0.92(s,9H), 1.20-2.06(m,7H), 2.18(dd,J=18.3,8.1 Hz,1H), 2.38-2.75(m,6H),3.90(s,3H), 3.96-4.22(m,2H), 5.46-5.69(m,2H), 7.10-7.35(m,7H),7.87-8.00(m,2H)

IR(neat):3027,2953,2930,2857,1745,1724,1611,1497,1472,1463,1436,1414,1362,1310,1279,1252,1179,1155,1111,1021,1007,972,940,888,838,777,700,670 cm⁻¹

(3) To an acetonitrile solution (840 ml) of the compound obtained in (2)(16.75 g) was added 46% aqueous hydrofluoric acid solution (189 ml) at0° C., followed by stirring at the same temperature for an hour. Thereaction solution was poured into a mixture of ethyl acetate (500 ml)and a saturated aqueous sodium bicarbonate solution (5.7 1) withstirring, and the aqueous layer was extracted with ethyl acetate. Theresulting organic layer was dried over anhydrous magnesium sulfate andfiltered. The filtrate was concentrated under reduced pressure, and theresulting crude product was purified by a silica gel columnchromatography (developing solvent; hexane:ethyl acetate=1:4) to givethe title compound (8.91 g).

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.48-2.06(m,9H), 2.22(dd,J=18.5,9.6 Hz,1H),2.34(dt,J=12.0,8.6 Hz,1H), 2.54-2.80(m,4H), 2.74(dd,J=18.5,7.5 Hz,1H),3.88(s,3H), 3.99-4.17(m,2H), 5.56(dd,J=15.4,8.6 Hz, 1H),5.69(dd,J=15.4,6.6 Hz,1H), 7.09-7.33(m,7H), 7.86-7.97(m,2H)

IR(neat):3400,3062,3027,2943,2860,1715,1610,1574,1496,1455,1436,1416,1373,1282,1180,1157,1111,1071,1021,971,917,859, 765,702,636cm⁻¹

EXAMPLE 22-Decarboxy-2,3,4,18,19,20-hexanor-5-(2-trifluoromethylphenyl)-17-phenyl-PGE₁(Compound 16)

(1) Following the substantially same manner as in Example 1(2) using2-(2-trifluoromethylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(2-trifluoromethylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; −0.02(s,3H), 0.04(s,9H),0.86(s,9H),0.91(s,9H),1.57-1.86(m,6H),1.91-2.06(m,1H),2.18(dd,J=18.3,8.0Hz,1H),2.40-2.84(m,6H),3.99-4.25(m,2H),5.47-5.71(m,2H),7.09-7.63(m,9H)

IR(neat);2954,2930,2886,2857,1745,1607,1583,1495,1471,1462,1362,1314,1255,1158,1122,1061,1037,1006,972,939,837,776,746,699,670,654,599 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm;1.40-1.92(m,10H),1.96-2.10(m,1H),2.22(dd,J=18.6,9.6Hz,1H),2.26-2.48(m,1H),2.58-2.84(m,5H),3.97-4.20(m,2H),5.57(dd,J=15.3,8.6 Hz,1H), 5.73(dd,J=15.3,6.5 Hz,1H), 7.10-7.60(m,9H)

IR(neat);3368,3027,2927,2864,1742,1606,1583,1495,1454,1314,1163,1118,1060,1034,971,768,746,700,653,600,478 cm⁻¹

EXAMPLE 32-Decarboxy-2,3,4,18,19,20-hexanor-5-(3-trifluoromethylphenyl)-17-phenyl-PGE₁(Compound 17)

(1) Following the substantially same manner as in Example 1(2) using2-(3-trifluoromethylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(3-trifluoromethylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm;−0.05-0.15(m,12H),0.75-2.80(m,14H),0.86(s,9H),0.91(s,9H),4.00-4.25(m,2H),5.45-5.70(m,2H),7.10-7.50(m,9H)

IR(neat);3027,2953,2930,2895,2858,1745,1603,1495,1472,1462,1406,1361,1328,1254,1199,1164,1126,1075,1006,972,939,884,837,801,777,749,701,665 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 0.80-2.81(m,11H),2.12-2.42(br,1H),2.22(dd,J=18.6,9.7 Hz,1H), 2.34(dt,J=12.0,8.6 Hz,1H),2.74(ddd,J=18.6,7.5,1.1 Hz,1H),3.03(brs,1H),3.97-4.18(m,2H),5.55(dd,J=15.4,8.5 Hz,1H),5.68(dd,J=15.4,6.8 Hz,1H),7.11-7.46(m,9H)

IR(neat);3368,3027,2930,2861,1742,1603,1495,1453,1328,1199,1162,1123,1073,1031,971,900,800,749,701,661,581 cm⁻¹

EXAMPLE 42-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-trifluoromethylphenyl)-17-phenyl-PGE₁(Compound 18)

(1) Following the substantially same manner as in Example 1(2) using2-(4-trifluoromethylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-trifluoromethylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.04(s,12H), 0.86(s,9H), 0.91(s,9H),1.14-2.06(m,9H), 2.17(dd,J=18.3,8.0 Hz,1H), 2.38-2.78(m,6H),3.99-4.26(m,2H), 5.45-5.68(m,2H), 7.08-7.34(m,7H), 7.45-7.54(m,2H)

IR(neat);3028,2954,2930,2858,1745,1619,1497,1472,1463,1362,1327,1255,1164,1124,1069,1020,1007,972,939,888,837,777,748, 699,670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.48-2.06(m,9H), 2.22(dd,J=18.6,9.7 Hz,1H),2.29-2.41(m,1H), 2.55-2.80(m,5H), 3.99-4.18(m,2H), 5.56(dd,J=15.3,8.5Hz,1H), 5.70(dd,J=15.3,6.6 Hz,1H), 7.12-7.34(m,7H), 7.42-7.49(m,2H)

IR(neat):3369,3027,2931,2862,1742,1618,1496,1455,1418,1327,1162,1120,1068,1019,972,846,751,701 cm⁻¹

EXAMPLE 52-Decarboxy-2,3,18,19,20-pentanor-4-(4-methylphenyl)-17-phenyl-PGE₁(Compound 25)

(1) Following the substantially same manner as in Example 1(2) using3-(4-methylphenyl)propyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,18,19,20-pentanor-4-(4-methylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.02(s,3H), 0.05(2s,6H), 0.06(s,3H),0.87(s,9H), 0.91(s,9H), 1.14-2.02(m,9H), 2.18(dd,J=18.2,8.1 Hz,1H),2.30(s,3H),2.37-2.75(m,6H),3.96-4.25(m,2H),5.46-5.70(m,2H),6.94-7.34(m,9H)

IR(neat);3025,2953,2929,2857,1745,1604,1515,1496,1471,1462,1406,1361,1252,1154,1100,1006,971,939,877,837,808,776,748,699,670,544,488 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.20-2.80(m,17H), 2.22(dd,J=18.3,9.6Hz,1H), 2.30(s,3H), 3.98-4.20(m,2H), 5.56(dd,J=15.4,8.5 Hz,1H),5.71(dd,J=15.4,6.6 Hz,1H), 6.98-7.08(m,4H), 7.14-7.33(m,5H)

IR(KBr);3439,3026,2923,2855,1732,1603,1515,1498,1455,1357,1243,1151,1085,992,970,806,775,748,717,699,578,486 cm⁻¹

EXAMPLE 62-Decarboxy-2,3,4,18,19,20-hexanor-5-(2-methylphenyl)-17-phenyl-PGE₁(Compound 27)

(1) Following the substantially same manner as in Example 1(2) using2-(2-methylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(2-methylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; −0.05-0.10(m,12H), 0.75-2.80(m,14H),0.86(s,9H), 0.91(s,9H), 2.26(s,3H), 3.98-4.30(m,2H), 5.45-5.70(m,2H),7.00-7.35(m,9H)

IR(neat);3063,3026,2953,2930,2886,2857,1745,1604,1495,1471,1462,1361,1253,1155,1103,1006,972,939,886,837,776,745,699, 670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 0.80-3.04(m,15H), 2.21(dd,J=18.4,9.7Hz,1H), 2.25(s,3H), 3.96-4.24(m,2H), 5.54(dd,J=15.3,8.6 Hz,1H),5.68(dd,J=15.3,6.8 Hz,1H), 6.98-7.36(m,9H)

IR(neat);3369,3061,3025,2932,2862,1741,1639,1603,1494,1455,1347,1244,1157,1074,1030,971,915,746,700,580,495,453 cm⁻¹

EXAMPLE 72-Decarboxy-2,3,4,18,19,20-hexanor-5-(3-methylphenyl)-17-phenyl-PGE₁(Compound 28)

(1) Following the substantially same manner as in Example 1(2) using2-(3-methylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(3-methylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.04(2s,6H), 0.05(s,6H), 0.86(s,9H),0.91(s,9H), 1.20-1.87(m,6H), 1.90-2.04(m,1H), 2.17(dd,18.2,8.1 Hz,1H),2.30(s,3H), 2.40-2.74(m,6H), 3.98-4.25(m,2H), 5.45-5.68(m,2H),6.88-7.34(m,9H)

IR(neat);3026,2953,2929,2857,1745,1606,1495,1471,1462,1361,1253,1155,1098,1006,972,939,882,837,776,748,699,670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm;1.40-2.10(m,9H),2.12-2.82(m,6H),2.21(dd,J=18.5,9.7Hz,1H),2.28(s,3H),3.98-4.20(m,2H),5.56(dd,J=15.4,8.4Hz,1H),5.71(dd,J=15.4,6.2 Hz,1H), 6.89-7.35(m,9H)

IR(neat);3368,3025,2925,2859,1741,1606,1495,1455,1348,1247,1156,1072,1031,971,914,782,748,700,580,488 cm⁻¹

EXAMPLE 82-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-methylphenyl)-17-phenyl-PGE₁(Compound 29)

(1) Following the substantially same manner as in Example 1(2) using2-(4-methylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-methylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.04(s,9H), 0.05(s,3H), 0.86(s,9H),0.91(s,9H), 1.50-2.03(m,8H), 2.16(dd,J=18.2,8.1 Hz,1H), 2.29(s,3H),2.40-2.70(m,5H), 3.96-4.24(m,2H),5.44-5.62(m,2H),7.04(s,4H),7.10-7.34(m,5H)

IR(neat):3026,2953,2929,2857,1746,1604,1516,1497,1472,1463,1407,1361,1253,1155,1116,1006,972,939,887,837,776,699, 670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.49-2.06(m,9H), 2.21(dd,J=18.5,9.8 Hz,1H),2.26(s,3H), 2.28-2.42(m,1H), 2.45-2.79(m,5H),3.99-4.17(m,2H),5.55(dd,J=15.3,8.4 Hz,1H), 5.69(dd,J=15.3,6.6 Hz,1H), 7.01(s,4H),7.12-7.34(m,5H)

IR(KBr):3502,3380,3028,2924,2856,1730,1516,1498,1454,1366,1316,1160,1086,1030,990,972,900,788,748,700 cm⁻¹

Example 92-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-acetylphenyl)-17-phenyl-PGE₁(Compound 31)

(1) Following the substantially same manner as in Example 1(2) using2-(4-acetylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-acetylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃, 200 MHz) δ ppm; −0.04-0.09(m,12H), 0.86(s,9H),0.91(s,9H),1.16-2.26(m,8H),2.38-2.72(m,6H),2.57(s,3H),4.00-4.24(m,2H),5.47-5.70(m,2H),7.10-7.34(m,7H),7.81-7.93(m,2H)

IR(neat);3027,2953,2929,2857,1743,1684,1607,1571,1496,1471,1462,1411,1359,1267,1182,1155,1097,1006,971,887,837,776,749,699,669,597 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.78-3.03(m,13H), 2.22(dd,J=18.7,9.7Hz,1H), 2.52(s,3H),2.64(t,J=7.6 Hz,2H), 3.94-4.21(m,2H),5.56(dd,J=15.4,8.1 Hz,1H), 5.70(dd,J=15.4,6.4 Hz,1H), 7.10-7.35(m,7H),7.76-7.86(m,2H)

IR(neat);3399,3085,3060,3026,2928,2860,1740,1678,1606,1570,1495,1455,1413,1359,1305,1271,1182,1156,1073,1030,1017,971,916,846,820,751,701,666,598,582,510 cm⁻¹

EXAMPLE 102-Decarboxy-2,3,18,19,20-pentanor-4-(4-methoxyphenyl)-17-phenyl-PGE₁(Compound 41)

(1) Following the substantially same manner as in Example 1(2) using3-(4-methoxyphenyl)propyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,18,19,20-pentanor-4-(4-methoxyphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.02(s,3H), 0.05(2s,6H), 0.06(s,3H),0.87(s,9H), 0.91(s,9H), 1.17-2.02(m,9H), 2.19(dd,J=18.2,8.1 Hz,1H),2.39-2.74(m,6H), 3.78(s,3H), 3.98-4.24(m,2H), 5.56(dd,J=15.2,6.7 Hz,1H),5.64(dd,J=15.2,4.4 Hz,1H), 6.75-6.86(m,2H),7.00-7.34(m,7H)

IR(neat);3027,2953,2930,2856,1744,1613,1584,1512,1463,1362,1300,1248,1177,1154,1104,1040,1006,971,939,877,837,776,749,699,670,559,519 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 1.14-2.88(m,17H), 2.22(dd,J=18.5,9.7Hz,1H), 3.77(s,3H),3.93-4.24(m,2H), 5.56(dd,J=15.4,8.1Hz,1H),5.71(dd,J=15.4,6.4 Hz,1H),6.72-6.86(m,2H),6.97-7.37(m,7H)

IR(neat);3428,3032,2933,2856,1733,1611,1584,1512,1463,1455,1357,1299,1244,1180,1152,1087,1035,992,970,814,752,721, 702,577,517cm⁻¹

EXAMPLE 112-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-methoxyphenyl)-17-phenyl-PGE₁(Compound 43)

(1) Following the substantially same manner as in Example 1(2) using2-(4-methoxyphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-methoxyphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; −0.05-0.10(m,12H), 0.75-2.75(m,14H),0.85(s,9H), 0.90(s,9H), 3.75(s,3H), 3.95-4.25(m,2H),5.45-5.70(m,2H),6.70-6.86(m,2H),6.98-7.35(m,7H)

IR(neat);3062,3027,2953,2930,2857,1744,1613,1584,1513,1462,1362,1300,1248,1177,1154,1116,1039,1006,972,939,887,837,776,750,699,670,519 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.20-2.80(m,13H), 2.22(dd,J=18.6,9.6Hz,1H), 2.37(dt,J=12.0,8.6 Hz,1H), 3.74(s,3H), 3.97-4.20(m,2H),5.56(dd,J=15.4,8.5 Hz,1H), 5.70(dd,J=15.4,6.5Hz,1H),6.73-6.80(m,2H),7.00-7.08(m,2H),7.14-7.34(m,5H)

IR(neat);3363,3028,2920,2856,1718,1611,1584,1512,1457,1341,1318,1301,1245,1178,1091,1031,971,887,810,754,705,524, 492 cm ⁻¹

EXAMPLE 122-Decarboxy-2,3,18,19,20-pentanor-4-(4-hydroxyphenyl)-17-phenyl-PGE₁(Compound 44)

(1) Following the substantially same manner as in Example 1(2) using3-(4-hydroxyphenyl)propyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,18,19,20-pentanor-4-(4-hydroxyphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.02(s,3H),0.05(s,3H),0.06(2s,6H),0.87(s,9H),0.91(s,9H),1.16-2.01(m,9H), 2.18(dd,J=18.3,8.1Hz,1H),2.39-2.72(m,6H),3.99-4.24(m,2H), 4.53(s,1H),5.54(dd,J=15.4,6.6Hz,1H),5.63(dd,J=15.4,4.3 Hz,1H), 6.66-6.78(m,2H),6.95-7.34(m,7H)

IR(neat);3400,3026,2953,2930,2857,1733,1614,1515,1496,1471,1462,1361,1254,1170,1102,1006,971,939,837,776,699,670, 551,504 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.78-2.85(m,17H), 2.23(dd,J=18.6,9.6Hz,1H),3.96-4.23(m,2H), 4.69(s,1H), 5.56(dd,J=15.3,8.1Hz,1H),5.70(dd,J=15.3,6.0Hz,1H),6.63-6.75(m,2H),6.92-7.04(m,2H),7.13-7.37(m,5H)

IR(neat);3410,3160,2937,2857,1733,1615,1594,1515,1499,1440,1366,1339,1256,1218,1160,1083,1030,990,973,885,829,816,780,731,700,576,510 cm⁻¹

EXAMPLE 132-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-hydroxyphenyl)-17-phenyl-PGE₁(Compound 45)

(1) Following the substantially same manner as in Example 1(2) using2-(4-hydroxyphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-hydroxyphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm;−0.05-0.10(m,12H),0.75-2.75(m,14H),0.85(s,9H),0.90(s,9H),3.95-4.25(m,2H),4.60(s,1H),5.43-5.70(m,2H),6.60-6.80(m,2H),6.90-7.20(m,7H)

IR(neat);3399,3026,2953,2929,2857,1734,1614,1515,1496,1471,1461,1362,1254,1170,1102,1006,972,939,886,837,776,748, 699,670,551cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.21-2.80(m,13H), 2.21(dd,J=18.4,9.7Hz,1H),2.35(dt,J=12.2,8.5 Hz,1H),2.74(ddd, J=18.4,7.6,1.2Hz,1H),3.98-4.17(m,2H),4.77(s,1H), 5.53(dd,J=15.4,8.5Hz,1H),5.66(dd,J=15.4,6.6Hz,1H),6.60-6.67(m,2H),6.93-7.01(m,2H),7.14-7.35(m,5H)

IR(neat);3368,2920,2857,1724,1655,1613,1515,1455,1400,1249,1156,1096,1029,988,837,744,699,620,561,526 cm⁻¹

EXAMPLE 142-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-fluorophenyl)-17-phenyl-PGE₁(Compound 50)

(1) Following the substantially same manner as in Example 1(2) using2-(4-fluorophenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-fluorophenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.00(s,3H),0.04(s,6H),0.05(s,3H),0.06(s,3H),0.86(s,9H),0.91(s,9H),1.46-1.87(m,6H),1.89-2.04(m,1H),2.17(dd,J=18.2,8.1Hz,1H),2.38-2.74(m,6H),3.98-4.24(m,2H),5.46-5.69(m,2H),6.84-7.35(m,9H)

IR(neat);3027,2953,2930,2857,1745,1602,1510,1471,1462,1406,1362,1253,1222,1156,1099,1006,972,939,887,837,776,749,699, 670,544,499cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 1.40-2.08(m,8H), 2.21(dd,J=18.5,9.7Hz,1H),2.12-2.44(m,1H),2.46-2.83(m,6H),3.97-4.22(m,2H),5.56(dd,J=15.4,8.1 Hz,1H), 5.70(dd,J=15.4,6.3Hz,1H),6.82-7.36(m,9H)

IR(neat);3368,3026,2929,2859,1741,1602,1509,1455,1348,1220,1157,1072,1031,971,830,750,700,545 cm⁻¹

EXAMPLE 152-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-hydroxymethylphenyl)-17-phenyl-PGE₁(Compound 55)

(1) Following the substantially same manner as in Example 1(2) using2-(4-hydroxymethylphenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-hydroxymethylphenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.04,0.05 and 0.09(3s,18H),0.86(s,9H),0.91(s,9H),0.93(s,9H),1.13-2.78(m,13H), 2.17(dd,J=18.4,8.0Hz,1H),3.98-4.26(m,2H),4.69(s,2H),5.45-5.73(m,2H),7.04-7.34(m,9H)

IR(neat);3026,2954,2929,2886,2857,1745,1604,1514,1496,1471,1462,1362,1254,1096,1006,971,939,837,776,699,669 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 1.06-2.81(m,16H), 2.21(dd,J=18.4,9.6Hz,1H),3.99-4.18(m,2H),4.59(s,2H), 5.54(dd,J=15.4,8.0Hz,1H),5.63(dd,J=15.4,6.1 Hz,1H),7.09-7.33(m,9H)

IR(KBr);3348,2941,1722,1515,1497,1457,1436,1348,1320,1270,1247,1159,1066,1032,1009,973,848,810,755,731,700,487,471 cm⁻¹

EXAMPLE 162-Decarboxy-2,3,4,18,19,20-hexanor-5-(4-(N,N-dimethylamino)phenyl)-17-phenyl-PGE₁(Compound 57)

(1) Following the substantially same manner as in Example 1(2) using2-(4-(N,N-dimethylamino)phenyl)ethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby2-decarboxy-2,3,4,18,19,20-hexanor-5-(4-(N,N-dimethylamino)phenyl)-17-phenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.01(s,3H),0.03(s,3H),0.04(s,3H),0.05(s,3H),0.86(s,9H),0.91(s,9H),1.40-1.88(m,6H),1.90-2.04(m,1H),2.16(dd,J=18.2,8.1Hz,1H),2.37-2.73(m,6H),2.89(s,6H),3.94-4.24(m,2H),5.45-5.70(m,2H),6.61-6.73(m,2H),6.96-7.04(m,2H),7.11-7.34(m,5H)

IR(neat);3026,2953,2929,2856,2800,1744,1616,1567,1521,1496,1472,1461,1360,1252,1161,1098,1006,972,947,887,837,776,748, 699,670,550cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 1.47-2.11(m,9H), 2.21(dd,J=18.5,9.7Hz,1H),2.26-2.83(m,6H),2.88(s,6H),3.97-4.22(m,2H),5.56(dd,J=15.4,8.2Hz,1H),5.70(dd,J=15.4,6.2 Hz,1H),6.58-6.71(m,2H),6.98-7.08(m,2H),7.13-7.38(m,5H)

IR(KBr);3356,2934,2883,1741,1615,1519,1497,1455,1323,1267,1241,1208,1143,1070,990,972,947,830,808,775,758,725,706,513 cm⁻¹

EXAMPLE 17 2-Decarboxy-2,3,18,19,20-pentanor-4,17-diphenyl-PGE₁(Compound 38)

(1) Following the substantially same manner as in Example 1(2) using3-phenylpropyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby 2-decarboxy-2,3,18,19,20-pentanor-4,17-diphenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.02(s,3H),0.05(2s,6H),0.06(s,3H),0.87(s,9H),0.91(s,9H),1.16-2.76(m,15H), 2.18(dd,J=18.2,8.1Hz,1H),3.98-4.28(m,2H), 5.54(dd,J=15.4,6.4 Hz,1H), 5.64(dd,J=15.4,4.2Hz,1H),7.08-7.34(m,10)

IR(neat);3063,3027,2953,2930,2857,1745,1604,1496,1471,1462,1362,1253,1155,1098,1006,971,939,875,837,776,748,699, 670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 1.21-2.86(m,17H), 2.22(dd,J=18.5,9.7Hz,1H),3.96-4.26(m,2H), 5.56(dd,J=15.3,8.1 Hz,1H),5.71(dd,J=15.3,6.3Hz,1H),7.06-7.36(m,10H)

IR(KBr);3376,3027,2932,2856,1947,1729,1719,1603,1497,1455,1333,1285,1176,1150,1094,1071,981,909,885,841,744,699,586, 490,473 cm⁻¹

EXAMPLE 18 2-Decarboxy-2,3,4,18,19,20-hexanor-5,17-diphenyl-PGE₁(Compound 36)

(1) Following the substantially same manner as in Example 1(2) using2-phenylethyl zinc (II) iodide in place of2-(4-methoxycarbonylphenyl)ethyl zinc (II) iodide in Example 1(2),thereby 2-decarboxy-2,3,4,18,19,20-hexanor-5,17-diphenyl-PGE₁11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; −0.04-0.09(m,12H),0.86(s,9H),0.91(s,9H),1.20-2.05(m,7H),2.17(dd,J=18.3,8.0Hz,1H),2.44-2.74(m,6H),3.98-4.28(m,2H),5.46-5.69(m,2H),7.09-7.36(m,10H)

IR(neat);3063,3027,2953,2929,2857,1745,1604,1496,1471,1462,1361,1253,1155,1098,1006,972,939,837,776,748,699,670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.78-2.88(m,15H), 2.21(dd,J=18.6,9.8Hz,1H), 3.96-4.28(m,2H),5.46-5.86(m,2H),7.06-7.37(m,10H)

IR(neat);3368,3084,3061,3026,2929,2859,1732,1639,1603,1495,1454,1405,1345,1245,1156,1074,1030,971,914,749,699,582,488 cm⁻¹

EXAMPLE 192,3,4,18,19,20-Hexanor-1,5-inter-p-phenylene-17-phenyl-13,14-didehydro-PGE₁methyl ester (Compound 74)

(1) To a toluene solution (22 ml) of(3S)-3-(tert-butyldimethylsiloxy)-5-phenyl-1-pentyne (1.96 g) was addedn-butyl lithium (2.5 M, hexane solution, 2.64 ml) at 0° C., followed bystirring at room temperature for 30 minutes. To the solution was addeddiethylaluminum chloride (0.95 N, hexane solution, 8.10 ml) at 0° C.,followed by stirring at room temperature for 30 minutes. To the solutionwas added(4R)-2-(N,N-diethylamino)methyl-4-(tert-butyldimethylsiloxy)cyclopent-2-en-1-one(0.25 M, toluene solution, 22.0 ml) at room temperature, followed bystirring for 15 minutes. The reaction solution was poured into a mixtureof hexane (53 ml), a saturated aqueous ammonium chloride solution (53ml) and an aqueous hydrochloric acid solution (3 N, 15.4 ml) withstirring, and the organic layer was separated and washed with asaturated aqueous sodium bicarbonate solution (20 ml). The resultingorganic layer was dried over anhydrous magnesium sulfate, filtered andconcentrated, and the resulting residue was purified by a silica gelcolumn chromatography (developing solvent; hexane:ethyl acetate=49:1) togive(3R,4R)-2-methylene-3-[(3S)-3-tert-butyldimethylsiloxy-5-phenylpent-1-ynyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-one(1.65 g).

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.09(s,3H), 0.11(s,6H), 0.14(s,3H),0.90(s,9H)0.91(s,9H), 1.90-2.07(m,2H), 2.33(dd,J=17.9,7.4 Hz,1H),2.62-2.85(m,2H), 2.72(dd,J=17.9,6.7 Hz,1H), 3.50-3.60(m,1H),4.21-4.35(m,1H), 4.42(dt,J=1.5 Hz,6.4 Hz,1H), 5.57(dd,J=2.5,0.6 Hz,1H),6.12-6.18(m,1H),7.12-7.36(m,5H)

IR(neat);2955,2930,2896,2857,2245,1735,1645,1472,1391,1223,1250,1124,1090,1072,838,778 cm⁻¹

(2) Following the substantially same manner as in Example 1(2) using thecompound obtained in the above (1), thereby2,3,4,18,19,20-hexanor-1,5-inter-p-phenylene-17-phenyl-13,14-didehydro-PGE₁methyl ester 11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm; 0.07(s,3H), 0.08(s,6H), 0.11(s,3H),0.87(s,9H), 0.90(s,9H), 1.18-1.32(m,2H), 1.50-2.29(m,5H),2.16(dd,J=18.3,6.9 Hz,1H), 2.54-2.79(m,6H), 3.90(s,3H), 4.22-4.42(m,1H),4.37(dt,J=1.6,6.3 Hz,1H), 7.11-7.35(m,7H), 7.88-7.98(m,2H)

IR(neat):2953,2930,2896,2858,2236,1748,1724,1611,1497,1472,1463,1436,1414,1362,1310,1280,1253,1179,1109,1021,1006,969,940,838,779,701,671 cm⁻¹

(3) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (2), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.54-2.10(m,6H),2.13(br s,1H),2.20-2.31(m,1H), 2.22(dd,J=18.6,9.2 Hz,1H), 2.64(ddd,J=11.4,8.2,1.8Hz,1H), 2.68(t,J=7.4 Hz,2H), 2.75(t,J=7.8 Hz,2H),2.76(ddd,J=18.6,7.2,1.3 Hz,1H), 2.82(br s,1H), 3.89(s,3H),4.25-4.43(m,2H), 7.13-7.33(m,7H), 7.89-7.95(m,2H)

IR(neat):3420,3027,2947,2862,2236,1744,1720,1610,1497,1437,1415,1283,1180,1154,1111,1063,1021,858,764,702 cm⁻¹

EXAMPLE 202,3,4,18,19,20-Hexanor-1,5-inter-p-phenylene-17-phenyl-13,14-didehydro-PGE₁(Compound 75)

An acetone solution (43 ml) of(3R,4R)-2-methylene-3-[(3S)-3-tert-butyldimethylsiloxy-5-phenylpent-1-ynyl]-4-(tert-butyldimethylsiloxy)cyclopentan-1-oneobtained in Example 1(1) (494 mg), 4-(2-iodoethyl)benzoic acid (1.49 g),tributyltin hydride (1.45 ml) and triethyl borane (1.0 M, hexanesolution, 0.18 ml) was stirred at 10° C. overnight. The reactionsolution was applied to a silica gel column chromatography (developingsolvent; hexane:ethyl acetate=7:3) to give the crude product, followedby the substantially same manner as in Example 1(3), thereby titlecompound was obtained (176 mg).

¹H-NMR(CDCl₃,300 MHz) δ ppm; 1.53-2.08(m,6H), 2.16-2.36(m,1H),2.23(dd,J=18.6,9.1 Hz,1H), 2.59-2.84(m,4H), 2.75(t,J=7.7 Hz,2H),4.24-4.43(m,1H), 4.39(dt,J=1.7,6.6 Hz,1H), 7.13-7.33(m,7H),7.93-8.05(m,2H)

IR(neat):3391,3026,2931,2862,2238,1740,1693,1611,1575,1497,1455,1419,1315,1286,1179,1063,1020,919,858,756,701,668,605, 532 cm⁻¹

Comparative Example(2E)-18,19,20-Trinor-17-phenyl-2,3,13,14-tetradehydro-PGE₁ methyl ester

(1) Following the substantially same manner as in Example 1(2) using thecompound obtained in Example 19(1) and (4E)-5-methoxycarbonylpent-4-enylzinc (II) iodide in place of 2-(4-methoxycarbonylphenyl)ethyl zinc (II)iodide in Example 1(2), thereby(2E)-18,19,20-trinor-17-phenyl-2,3,13,14-tetradehydro-PGE₁ methyl ester11,15-bis(tert-butyldimethylsilyl ether) was obtained.

¹H-NMR(CDCl₃,200 MHz) δ ppm: 0.09(s,6H), 0.11(s,3H), 0.13(s,3H),0.89(s,9H), 0.91(s,9H), 1.36-1.86(m,6H), 1.90-2.04(m,2H),2.09-2.28(m,3H), 2.17(dd,J=18.2,7.0 Hz,1H), 2.60-2.80(m,4H), 3.71(s,3H),4.23-4.35(m,1H), 4.39(dt,J=1.5,6.4 Hz,1H), 5.81(dt,J=15.7,1.5 Hz,1H),6.95(dt,J=15.7,6.4 Hz,1H), 7.13-7.34(m,5H)

IR(neat):3027,2952,2930,2858,2235,1748,1728,1658,1605,1497,1472,1463,1436,1385,1362,1315,1254,1094,1046,1006,750,940,838,779,751,700,670 cm⁻¹

(2) Following the substantially same manner as in Example 1(3) using thecompound obtained in the above (1), thereby the title compound wasobtained.

¹H-NMR(CDCl₃,300 MHz) δ ppm: 1.36-1.88(m,6H), 1.92-2.30(m,3H),2.23(dd,J=18.5,9.1 Hz,1H), 2.64(ddd,J=1.4,8.4,1.6 Hz,1H),2.69-2.84(m,1H), 2.80(t,J=7.6 Hz,2H), 3.72(s,3H), 4.25-4.46(m,2H),5.82(dt,J=15.6,1.2 Hz,1H), 6.95(dt,J=15.6,7.1 Hz,1H), 7.17-7.33(m,5H)

IR(neat):3419,3026,2932,2860,2235,1745,1724,1657,1497,1455,1438,1277,1203,1157,1039,920,752,702 cm⁻¹

Formulation Example 1

Per capsule, Compound 18 (100 μg), fine crystalline cellulose (190 mg)and amorphous silicic acid (10 mg) were well-mixed, and filled into ahard gelatin capsule to give a capsule preparation.

Formulation Example 2

Compound 29 (100 μg) was dissolved in soybean oil (300 mg) and mixedwith egg yolk lecithin (50 mg). After addition of glycerin (70 mg),water for injection was added to make up to 3 ml. The solution wasroughly emulsified by using a mixer, and emulsified at a pressure of8000 psi by using a homogenizer, filled into an ample, sterilized inhigh-pressure vapor to give an ample preparation.

Experiment

Determination of DNA synthesis inhibition activity of PGE₁ analogs tohuman vascular smooth muscle cells

On a 24 well-plate (manufactured by Corning Co.), 1×10⁴ cells/well ofquintic culture cells of vascular cells derived from normal human aorta(produced by Kurabo Co.) were inoculated and cultured for 2 days. Themedium was exchanged from the growth medium (SG2: produced by KuraboCo.) to the basal medium (SB2: produced by Kurabo Co.), and cultured for24 hours, to which was added the growth medium (SG2) containing anethanol solution of the test compound. ³H-thymidine (produced by DaiichiChemicals Co.) was added in an amount of 0.01 mci/well and, afterculturing for 24 hours, the cultured supernatant was removed by suction,followed by washing with a phosphate buffer solution (PBS).

5% Trichloroacetic acid (TCA) was added and, after allowing to stand at4° C. for 20 minutes, the mixture was washed once with TCA. The mixturewas washed with PBS, and dissolved in 0.5 N KOH. Intake of ³H-thymidinewas determined using 20 μl of KOH dissolving the cells whichincorporated ³H-thymidine in the nucleus by means of a liquidscintillation counter (manufactured by Hewlett-Packard Co.).

Results are shown in Table 2.

TABLE 2 IC₅₀ (μM) Compound 18 0.66 Compound 29 0.73 Comparative 4.36Compound Note: Compounds 18 and 29 in Table 2 are those prepared in theexamples as described above. The test compounds were each used as anethanol solution and compared with control (vehicle-treated group).

As a result, Compounds 18 and 29 were found to exhibit a high inhibitingactivity on the growth of human vascular smooth muscle cells.

What is claimed is:
 1. A prostaglandin analog represented by formula(I):

[wherein A is an ethylene group, a vinylene group or an ethynylenegroup, Y¹ and Y² are the same or different, and each a hydrogen atom, ahalogen atom, a cyano group, a C₁₋₃ aminoalkyl group, a C₁₋₆hydroxyalkyl group, NR⁵R⁶ (wherein R⁵ and R⁶ are the same or different,and each a hydrogen atom or a C₁₋₆ alkyl group), a hydroxyl group, aC₁₋₆ alkoxy group, a C₁₋₉ alkyl group, a C₁₋₆ alkyl group substitutedwith halogen(s) or a C₁₋₅ acyl group, R¹ and R² are the same ordifferent, and each a hydrogen atom, a halogen atom, a C₁₋₉ alkyl groupor a C₁₋₆ alkyl group substituted with halogen(s), m is an integer of 0to 6, and n is an integer of 0 to 3], a pharmaceutically acceptable saltthereof or a hydrate thereof.
 2. The prostaglandin analog of Formula (I)according to claim 1 wherein A is a trans-vinylene group; thepharmaceutically acceptable salt thereof or the hydrate thereof.
 3. Theprostaglandin analog of Formula (I) according to claim 1 wherein A is anethynylene group; the pharmaceutically acceptable salt thereof or thehydrate thereof.
 4. The prostaglandin analog of Formula (I) according toany one of claims 1 to 3 wherein m is an integer of 1 to 6; thepharmaceutically acceptable salt thereof or the hydrate thereof.